tbuckley/cabot-search huggingface dataset:
Prediction value of TRIM29 on immunotherapy in colorectal cancer.
Authors: Jing Han, Xue Zhang, Zhisong Fan, Long Wang, Li Feng, Dan Li, Jing Zuo, Yudong Wang, Xinliang Zhou, Jiayin Liu
Journal: Journal of Clinical Oncology (2022)

e15533 Background: Our previous study have found that TRIM29 expressed higher in right colon cancer than left colon cancer and rectal cancer.But the main functions of TRIM29 was not fully clarified.Bioinformatics can be used for exploring the biological function of a gene.So we further explored the molecular mechanism by using bioinformatics analysis.The results showed that TRIM29 correlated to immune dysfunction.Mismatch repair deficient(dMMR) is closely related to the efficacy of immunotherapy in colorectal cancer.We also used GEO data to explore the relationship between TRIM29 and dMMR.At last, clinical pathological data were used to explore the relationship between TRIM29 and tumor lymphocyte infiltration. Methods: At first, bioinformatics analysis was used to further explore the molecular mechanism of TRIM29.Hub genes correlated with TRIM29 and Reactome/KEGG Pathway of the hub genes were identified and performed using String database(http://string.embl.de/).TISIDB(http://cis.hku.hk/TISIDB/) was utilized to analyse the correlations between TRIM29 expression and tumor infiltrating lymphocytes, immunomodulator and chemokine.Then GEO public data including 583 sample size was download and used to confirm the correlation ship between TRIM29 expressed and pMMR/dMMR status.At last, HE sections of the 227 CRC patients were collected to explore the connection between TRIM29 and tumor infiltrating lymphocytes. Results: Functional annotations and immune activity analysis showed TRIM29 is related to tumor infiltrating lymphocytes and due to immune dysfunction in colorectal patients.For tumor infiltrating lymphocytes analyzing, elevated TRIM29 was significantly associated with Act_DC, iDC,monocyte, NK,NKT, pDC, Tcm_CD4, Tcm_CD8, Tem_CD8 and Th1 cell infltration in colorectal ( P&lt; 0.05), leading to a general increase in immune infiltration.For chemokines analyzing,elevated TRIM29 was significantly associated with high expression of CXCR1,CXCR2 and CXCR4( P&lt; 0.05).For immunostimulators analyzing,TRIM29 over-expression was significantly associated with C10orf54, CD70, CD276, HHLA2 and ICOSLG, causing immune imbalance( P&lt; 0.05).For immunoinhibitors analyzing, elevated TRIM29 expression was significantly associated with PD-L1, LGALS9, PD-1, PVRL2,TGFBR1,TIGIT and VTCN1( P&lt; 0.05).The HE results revealed that high TRIM29 protein expression was correlated with high tumor-infiltrating lymphocytes ( P= 0.0053).GSE39582 data analyzing results showed that dMMR patients expressed higher TRIM29 level than dMMR patients( P= 0.0014). Conclusions: High TRIM29 expression is related to tumor infiltrating lymphocytes and due to immune dysfunction in colorectal patients.Elevated TRIM29 expression up regulating immune checkpoint molecules after immune stimulation to avoid immune damage.TRIM29 may serve as a new biomarker for immunotherapy.
Study of the effectiveness of chemotherapy in patients with colorectal cancer depending on the location of the metastatic lesion.
Authors: Sergey Viktorovich Kamishov, Shakhnoza Khamoidinovna Niyozova
Journal: Journal of Clinical Oncology (2022)

e15540 Background: The reason for the increased interest in the chemotherapeutic treatment of metastatic colorectal cancer (CRC) is the steady increase in the incidence of this oncological pathology, as well as the high incidence of neglect of the tumor process in a significant proportion of patients in the absence of improvement in long-term treatment results. Methods: In 84 patients with metastatic CRC (mCRC), the clinical effect and toxicity of the FOLFOX4 and CAPOX regimens were studied. In 51 (60.7%) patients, multiple metastases in various organs were most common, in 18 (21.4%) - solitary, and only in 15 (17.9%) patients - solitary. Among the examined patients, men accounted for 46 (54.7%), women - 38 (45.2%). The average age of men was 57.2+0.2 years, women 65.4+0.4 years. Patients underwent 2-4 courses of treatment, after which the effect of PCT was evaluated according to the REGIST scale (2009). Results: Out of 84 patients with mCRC who received 2-4 courses of palliative chemotherapy according to the FOLFOX4 and CAPOX regimens, complete regression of the process was observed in 14 (16.7%) patients, partial regression in 34 (40.5%) patients, stabilization of the process in 19 (22.6%) and in 17 (20.2%) progression of the disease was revealed. At the same time, the highest objective response rate (PR + FR) was with metastases in the liver - 16 (76.1%) and lungs - 12 (63.1%). Of the 3 patients with brain metastases, stabilization was noted in 2 cases and progression of the process in 1 case. With combined distant metastases (lungs + liver and lungs + bones), there were 2-3 times more patients who were not sensitive to therapy than those who were sensitive. With combined distant metastases (lungs + liver and lungs + bones), there were 2-3 times more patients who did not respond to therapy than those who were sensitive to treatment. The “treatment sensitive” group included 48 (57.1%) patients with complete and partial regression. The “treatment-resistant” group consisted of 36 (42.9%) patients with progression and stabilization of the disease. Conclusions: The highest objective response rate (PR+FR) in patients with mCRC was with metastases in the liver - 16 (76.1%) and lungs - 12 (63.1%). The comparatively better results in metastatic lesions of the liver and lungs are obviously associated with a more developed blood supply to these organs, which leads to a better supply of chemotherapy drugs and the effectiveness of treatment. At the same time, the combination of localization of CRC metastatic lesions in various organs significantly worsens the results of treatment.
Increased oxidative stress alters coronary microvascular tone in exercising swine with multiple comorbidities
Authors: O Sorop, RWA Van Drie, J Van De Wouw, DJ Duncker, D Merkus
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Netherlands CardioVascular Research Initiative: an initiative with support of the Dutch Heart Foundation Introduction Diabetes mellitus (DM), chronic kidney disease (CKD) and hypercholesterolemia either alone or in combination, induce sustained systemic inflammation, increased oxidative stress and coronary endothelial dysfunction. The resulting alterations in microvascular tone may contribute to impaired myocardial perfusion in patients chronically affected by these comorbidities. Purpose We tested, in exercising swine, the hypothesis that increased production of reactive oxygen species (ROS) due to DM, CKD and high fat diet (HFD) results in loss of NO bioavailability in the coronary microvasculature leading to altered myocardial perfusion. Methods In 12 female swine, DM (streptozotocin 3x50mg/kg iv), CKD (renal embolization), and hypercholesterolemia (via high fat diet, HFD) were induced for 6 months (DM+HFD+CKD). 10 female healthy swine on normal pig chow served as controls (Normal). The role of ROS in the regulation of coronary flow was studied at rest and during graded treadmill exercise with or without ROS scavengers (MPG+Tempol). Results 6 months after the induction of comorbidities, DM+HFD+CKD animals had sustained hyperglycemia (19.5±1.1 vs 8.7±0.5mmol/L), renal dysfunction (plasma creatinine: 163±7 vs 120±3 µmol/l), hypercholesterolemia (12.7±2.1 vs 1.7±0.1mmol/l) and sustained systemic inflammation (TNF 52±5 vs 25±6 pg/ml, all P&amp;lt;0.05). Myocardial superoxide production was increased in DM+HFD+CKD animals due to NADPH oxidase activation and eNOS uncoupling, (Sorop et al, CVR 2018) and total antioxidant capacity was reduced (Fig. A), which was associated with a lower myocardial NO production, (P&amp;lt;0.05). In vivo experiments showed that myocardial oxygen delivery was impaired in DM+HFD+CKD swine at rest and during exercise, requiring an increased myocardial oxygen extraction (MO2ex) compared to Healthy (compare control runs in panels C and D, P&amp;lt;0.05), that is due to a loss of NO vasodilator influence (van de Wouw et al. BRIC 2021). Interestingly, scavenging of ROS had no effect in Healthy but resulted in increased MO2ex in DM+HFD+CKD (Fig. C, D), indicating that increased oxidative stress resulted in increased production of vasodilator ROS, most likely H2O2. The latter was also supported by an increase in ceramide production (138±34 vs 45±4 nmol/ml, P&amp;lt;0.05) and increased activity of catalase in the myocardium (Fig. B, P&amp;lt;0.05). Conclusion In swine, 6 months exposure to multiple comorbidities resulted in increased oxidative stress associated with impaired myocardial oxygen delivery, due to a loss of NO that was partially compensated for by increased H2O2-mediated coronary vasodilation.
Comprehensive genomic profiling to identify gene alterations in DNA repair pathway across solid tumors.
Authors: Kevin McDonnell, Gargi D. Basu, Jess W. Hoag, David W. Hall, Fadel S. Alyaqoub, Susan M. Dombrowski, Pawan Noel, Szabolcs Szelinger, Sameer S. Udhane, Min Wang, Janine R. LoBello, Snehal Govind Thakkar, Frederick L. Baehner, Christine Hong, Wai Park, Gregory Idos, Stacy W. Gray, Stephen B. Gruber
Journal: Journal of Clinical Oncology (2022)

3124 Background: Deleterious events in DNA damage response (DDR) are hallmarks of cancer associated with sensitivity to PARP inhibitors (PARPi) and immune checkpoint inhibitors (CPI). This study investigated DDR pathway alterations across solid tumors. Methods: Samples were sequenced with the Oncomap ExTra assay using tumor-normal paired whole-exome DNA sequencing to detect single base substitutions, indels, and copy number alterations that were clinically actionable, defined as associated with FDA approved drugs or clinical trial enrollment. Here, we report the frequency of MSI-high and TMB-high (&gt;10 mutations/Mb), and clinically-actionable alterations for the following 49 DDR genes: ARID1A, ATM, ATR, ATRX, BAP1, BARD1, BLM, BRCA1/2, BRIP1, CDK12, CHEK1/2, EPCAM, ERCC1/2/3/4/5, FANCA/C/D2/E/F/G/I/L/M, MLH1, MRE11A, MSH2/6, MUTYH, NBN, PALB2, PMS2, PPP2R2A, PTEN, RAD21/50/51/51B/51C/51D/52/54L, XRCC1/2/3. Results: Of the 6055 patient samples profiled, 1633 (27.0%) had clinically actionable alterations in DDR genes; DDR alterations varied from 0-64.3% across tumor types. For the 5657 samples with TMB/MSI data, 429 (7.6%) had high TMB and 193 (3.4%) were MSI-high; MSI-high samples were usually TMB-high (n = 180; 93.2%). The percent of cancers that were TMB-high or MSI-high varied from 0-64.8% and 0-20.8% respectively. Actionable BRCA1/2 gene alterations were present in 319 patients (5.3%, range 0-15.3%). Three cancers (biliary, brain and liver) had BRCA1/2 alterations in less than 2% of patients but across the 49 DDR genes alterations were present in more than 20% of patients, representing a greater than 10-fold difference. Across solid tumors, this analysis identifies a group of 1314 patients (21.7%) who harbor a DDR gene alteration other than BRCA1/2. Conclusions: Defective DNA repair as detected by deleterious alterations in DDR genes along with TMB/MSI status has the potential to guide clinicians to FDA-approved therapy or clinical trial enrollment in a large percentage of patients across solid tumor types.[Table: see text]
Peri-operative complications in patients treated with thermal ablation for T1 renal cell tumors: Descriptive analysis and independent predictors
Authors: S. Luzzago, F.A. Mistretta, G. Mauri, G. Cozzi, M. Fontana, G. Cordima, A. Lo Giudice, F.M.G. Botticelli, G. Marvaso, M. Ferro, D.V. Matei, B.A. Jereczek Fossa, F. Orsi, G. Musi, O. De Cobelli
Journal: European Urology (2022)
Poor Diagnostic Efficacy of Noninvasive Tests for Advanced Fibrosis in Obese or Younger Than 60 Diabetic NAFLD patients
Authors: Takanori Ito, Vy H. Nguyen, Taku Tanaka, Huiyul Park, Ming-Lun Yeh, Miwa Kawanaka, Taeang Arai, Masanori Atsukawa, Eileen L. Yoon, Pei-Chien Tsai, Hidenori Toyoda, Jee-Fu Huang, Linda Henry, Dae Won Jun, Ming-Lung Yu, Masatoshi Ishigami, Mindie H. Nguyen, Ramsey C. Cheung
Journal: Clinical Gastroenterology and Hepatology (2022)
Reducing inpatient mortality in patients with cancer through multidisciplinary review and targeted interventions.
Authors: Manan P Shah, Sarah K. Garrigues, Ali Raza Khaki, Jennifer Hansen, Vasu Divi, Douglas W. Blayney
Journal: Journal of Clinical Oncology (2022)

1524 Background: Excess inpatient mortality is a marker of poor quality in cancer care. We developed a multidisciplinary mortality review committee to review each inpatient death to determine key drivers of mortality and develop targeted interventions to reduce our inpatient mortality index. Methods: Through retrospective review, inpatient deaths were identified at Stanford Health Care for patients with an ICD10 cancer diagnosis regardless of inpatient service. Details of each hospitalization were reviewed by a quality consultant and subsequently reviewed by a physician quality team member to identify opportunities for improvement. Most cases were then discussed in a monthly multidisciplinary committee meeting. The committee analyzed key drivers of inpatient mortality, communicated suggestions to the patient’s outpatient and inpatient attending physicians, and/or identified opportunities for systemic change. The resulting targeted interventions were tracked using the observed versus expected mortality ratio for inpatient deaths over time. Results: From May 2017 through August 2021 we reviewed 528 inpatient oncology deaths. Patients’ median age was 65 years, and the median length of stay was 8 days. 73% of patients had metastatic cancer, and 28% received chemotherapy within 14 days of death. 25% of patients had a prior ED visit, and 35% had a prior hospitalization within 30 days of admission. Only 26% of patients had an advanced directive on record at time of death. Opportunities for improvement were identified for 60% of cases (Table). Interventions have aimed to increase advance care planning conversations and documentation, develop predictive models for cancer-related readmissions and mortality, expand outpatient services for urgent symptoms, and expedite transitions to hospice. Conclusions: Understanding key drivers for preventable inpatient mortality through a multidisciplinary review process identified targeted interventions that have successfully contributed to reduction of the inpatient cancer mortality index.[Table: see text]
DIPG-14. Neogenin Knockout Stops the Invasion and Dissemination of Diffuse Intrinsic Pontine Gliomas<i>in vivo</i>.
Authors: Julie Sesen, Aram Ghalali, Tyra Martinez, Jessica Driscoll, Katie Pricola Fehnel, Edward Smith
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Diffuse Intrinsic Pontine Glioma (DIPG) is a devastating high-grade glioma localized in the brainstem that occurs almost exclusively in children. The significant mortality rates of DIPG stem largely from its capacity to invade adjacent normal brain. We have previously published studies identifying the axon guidance factor, neogenin as a key driver regulating brain tumor cell invasion in medulloblastoma, glioblastoma and DIPG in vitro. Here we expand this work with an in vivo model to validate neogenin as promising inducer of DIPG invasion. METHODS: CRISPR-Cas9 system was used to knock-out the neogenin gene in DIPG cells. After validation of the knockout (KO) in vitro by RTqPCR, Western blot, and immunofluroresence, the cells were orthotopically implanted in the pons of nude mice (n=8/group) with a stereotactic frame. Tumor growth and dissemination were monitored using the In Vivo Imaging System (IVIS). Then, brains and spinal cords were collected, and H&amp;E staining was performed. RESULTS:In vitro studies confirmed the KO of neogenin in DIPG cells. In vivo studies revealed that the neogenin total KO group had no progression of the tumor without any dissemination after 4-6 weeks, in marked contrast to the WT group, which exhibited steady growth and widespread dissemination into the spine. Immunohistochemistry confirmed the IVIS results. CONCLUSION: Expanding on previous work, this data suggests that neogenin is a major contributor of DIPG cell invasion and dissemination. The blockade of neogenin in DIPG cells demonstrates the potential utility of neogenin as potential therapeutic target, capable of reducing tumor growth and stopping tumor cell dissemination.
Ovarian cancer mortality: implications of income-inequality and availability of medical doctors in Brazil.
Authors: Jean Henri Maselli-Schoueri, Luis Eduardo Werneck De Carvalho, Laercio da Silva Paiva, Manuela de Almeida Roediger, Luiz Carlos de Abreu, Fernando Luiz Affonso Fonseca, Claudia Vaz De Melo Sette, Fernando Adami
Journal: Journal of Clinical Oncology (2022)

e22520 Background: Ovarian cancer mortality varies by region and age group in Brazil. However, it is still unknown if socioeconomic inequalities may affect its outcome even if indirectly as it happens for other gynecologic neoplasms in the country. Methods: Ecological study conducted with secondary data from 2016-2018 to examine the relationship between income-inequality and the amount of doctors per inhabitant on ovarian cancer mortality in Brazil. All data were gathered from Brazil’s public health system. Mortality was analyzed by sex and age, which was standardized according to the World Health Organization’s population. Income-Inequality was measured using the Gini index, obtained from the United Nations Development Programme. The number of doctors was obtained from the Unified Health System and was also calculated as the rate per 100,000 inhabitants. Linear regression was performed using stepwise selection/backward elimination. Results: Despite income inequality as measured by the Gini index not having any statistically significant relationship with ovarian cancer mortality rates, we found that the amount of doctors per inhabitant was positively associated with ovarian cancer mortality rates (β 0.037, IC95% 0.028;0.045), whereas the amount of clinical oncologists (β-0.426, IC95% -0.805; -0.047) and higher income (β -0.004, IC95% -0.005; -0.003) were all negatively associated with those rates (p &lt; 0.05), meaning that the higher those variables, the lower the mortality. Conclusions: Ovarian cancer mortality differs among federative units in Brazil. Higher mortality is associated with a greater amount of doctors per inhabitant, whereas lower mortality rates were found to be associated with higher income and more clinical oncologists available.
Leveraging PrOFILE data to illustrate and benchmark the Institute of Medicine quality aims in global pediatric oncology.
Authors: Miriam Gonzalez-Guzman, Elizabeth Riley, Mai An Le, Heather Forrest, Paola Friedrich
Journal: Journal of Clinical Oncology (2022)

e18706 Background: PrOFILE is a dynamic 360 o evaluation of health service delivery that helps care teams and institutions committed to increasing childhood cancer survival define an improvement strategy. PrOFILE stands for Pediatric Oncology Facility Integrated Local Evaluation. As of December 2021, PrOFILE has been utilized in over 130 facilities from over 25 countries around the globe. The standard outputs are presented by module, which reflect the patient-care continuum. The Institute of Medicine (IOM) has proposed six aims for improvement to drive fundamental change in health care delivery. The IOM Committee recommends periodically evaluating progress and developing strategies for overcoming barriers.However, a tool to assist facilities to set a baseline and periodically assess progress does not exist. We evaluated the feasibility of leveraging PrOFILE data to identify (1) the status of each quality aim as defined by IOM and (2) the status compared to facilities in the same country or region. Methods: This study employed a multi-step mapping approach. We first mapped the 1,279 PrOFILE variables to the six IOM quality aims. Mapping was first performed independently by two authors, then reviewed by PrOFILE experts to achieve consensus. Each variable could only contribute to one aim. We then validated the mapping by running the previously collected data available from two cohorts (one with 13 and one with 17 facilities) and benchmarking institutional data to cohort data. Quality improvement experts and local stakeholders provided feedback on further use of the illustrations and benchmarks. Results: We identified 305 PrOFILE variables that reflect the IOM quality aims (Table). More PrOFILE questions could be used as proxy for safety, effectiveness, and timeliness aims, than patient-centeredness, efficiency, and equity (Table), however, all domains could be represented. Benchmarking the institution results to the regional or country cohort results allowed for context-relevant insightful benchmarking. Framing PrOFILE results utilizing the IOM six aims allowed local healthcare teams and relevant stakeholders to evaluate their baseline and set targets for improvement. Conclusions: This exercise demonstrates the feasibility of leveraging PrOFILE data to assess institutional alignment with the IOM quality aims. The results allow illustrating, benchmarking, and engaging with stakeholders in conversations aimed at improving delivery of pediatric oncology care in global real-world settings utilizing this perspective. Future PrOFILE reports will incorporate this feature, supporting establishing a baseline and tracking of progress over time.[Table: see text]
Cardiac remodeling in severe hypertension, does it respond to tight blood pressure control?
Authors: M El Tahlawi, S Salem, M Fahmy, M Tharwat
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: None. Background Severe hypertension (HTN) may cause target organ damage (TOD). Kidney can tolerate severe HTN to very high levels. Cardiac remodeling as TOD could be detected by elevation of biomarker Troponin. Aim We aim to detect the response of organs (heart &amp; kidney) to tight control of severe HTN. Patients &amp; Methods Patients admitted due to severe hypertension (BP&amp;gt; 180/120) associated with any symptoms were enrolled. All patients were managed according to the European guidelines to the target BP. Cardiac biomarker Hs-Troponin T (hs-TNT) and serum creatinine (s.creat) were measured for all patients on admission and 24 hours later. Results Ninty five patients with hypertensive crisis were treated to target BP. Forty six patients had initially high hs-TNT (Group A) and 49 patients had initially normal hs-TNT (Group B). There was a highly significant difference between both groups regarding initial and follow-up s.creat with higher values in Group B (P= 0.03 and 0.004 respectively).There was high significant difference between initial and follow up s.creat values in Group B with higher values in the follow up measurements after BP control to the target (P= 0.03), while this difference is insignificant in Group A (P=0.26). Five patients in Group B developed renal failure after tight BP control. There was a significant positive correlation between hs-TNT and the follow-up s.creat (P=0.018) with more deterioration of s.creat in those having initial high hs-TNT. Conclusion In severe HTN, hs-TNT may be elevated due to marked afterload. Renal affection and TOD occurs before cardiac remodeling and damage due to severe HTN. Renal autoregulation occurs in chronic elevation of BP. Acute control of severe HTN leads to disrruption of renal autoregulation and renal shut down. European guidelines regarding severe HTN control should be revised. In hypertensive patients with high hs-TNT, BP should not be well controlled on the short term not to disrupt renal autoregulation.